Dysregulated expression of specific growth factors and their receptors contributes to the aberrant growth of the prostate. One such receptor is the p75NTR, a cell surface protein that binds the neurotrophins (e.g. nerve growth factor). The p75NTR is a member of the tumor necrosis factor receptor super-family, of which many members share an intracellular sequence motif designated the "death domain" that can initiate apoptosis. Concomitantly, the p75NTR exhibits both tumor suppressor and metastasis suppressor activity in the prostate. During malignant progression of the prostate, we have shown reduced expression of the p75NTR protein facilitates aberrant growth. Conversely, ectopic re-expression of p75NTR in cells inhibits growth by induction of apoptosis. Significantly, even though expression of the p75NTR protein is suppressed in these cells, the gene encoding p75NTR is intact. Hence, increased p75NTR expression in cells, either by ectopic re-expression, or by alternate novel mechanisms, such as by induction with select aryl propionic acids such as carprofen, ibuprofen and r-flurbiprofen, restores its growth inhibitory activity. We show that the aryl propionic acid class of compounds is able to differentially restore p75NTR protein expression, which correlates with a significant decrease in the survival of the cells. Of all the aryl propionic acids tested for this activity, we have identified carprofen as a lead molecule with superior efficacy for induction of p75NTR dependent inhibition of growth. Hence, the synthesis of carprofen analogs can be used to produce unique compounds with a novel mechanism of action for p75NTR- dependent inhibition of growth. Significantly, our identification of a novel chemotherapeutic target, the p75NTR induced by carprofen analogs, meets a major need of drug discovery programs, that is, the desire for new molecular entities with a new mechanism of action. Based upon our publications and preliminary data, and in collaboration with a medicinal chemist (Dr. Alan Kozikowski) from the Drug Discovery Program, University of Illinois Chicago, we propose to test the hypothesis that the unique mechanism of action of carprofen analog induction of p75NTR tumor suppressor dependent inhibition of cell survival forms a basis for development of novel chemotherapeutic drugs for treatment of prostate cancer. This hypothesis will be evaluated in the following five specific aims. Aim 1: Use structure-activity relationships to drive medicinal chemistry of unique analogs of carprofen with enhanced efficacy for p75NTR dependent inhibition of growth. Aim 2: To demonstrate that carprofen analog(s) inhibition of prostate cancer cell growth is dependent on p75NTR expression. Aim 3: To demonstrate that carprofen analog(s) inhibition of prostate cancer cell growth is mediated via the p38 MAPK signal transduction pathway and is independent of cyclooxygenases (COXs). Aim 4: Screen a lead carprofen analog compound for maximum tolerable dose and toxicity/safety profile. Aim 5: Test a novel carprofen analog for inhibition of prostate cancer growth in the TRAMP murine model. By lead compound optimization, we anticipate the development of novel chemotherapeutics with a novel mechanism of action for the treatment of prostate cancer.